Cure of sickle cell disease (SCD) can be achieved by hematopoietic cell transplantation (HCT) but the morbidity and mortality of the procedure have precluded the more widespread use of this therapy. Graft failure remains one significant challenge unique to this population. In addition, SCD patients who undergo HCT generally have severe manifestations of the disease. Hence, they are more fragile and prone to complications. Graft-vs-host disease (GVHD), risk of infertility, neurologic toxicities and chronic pain are factors which negatively impact survival and quality of life post-HCT. Thus, the major challenges of HCT for SCD are to develop conditioning regimens that have minimize toxicity without compromising engraftment and to infuse grafts that do not elicit GVHD. We are pursuing an approach that minimizes the toxicities of allogeneic HCT by using a first-of-its-kind biologic agent, a monoclonal antibody (mAb) targeting the molecule CD117 (c-Kit) present on HSC as transplant conditioning, together with grafts of purified hematopoietic stem cells (HSC) isolated from mobilized peripheral blood. We are currently testing this approach in children with severe combined immunodeficiency (SCID). The ultimate goal is achieve safer and more effective HCT compared to standard approaches by reducing and/or eliminating the toxicities of chemoradiation conditioning and by utilizing grafts of purified HSC, devoid of T cells thereby avoiding the problem of GVHD. While this clinical study focuses on patients with SCID, our early clinical and preclinical data, lead us to conclude that this approach will become broadly applicable as curative therapy to many of the disorders of the blood, including SCD.